Design and synthesis of novel and potent GPR119 agonists with a spirocyclic structure

Bioorg Med Chem Lett. 2018 Apr 15;28(7):1228-1233. doi: 10.1016/j.bmcl.2018.02.044. Epub 2018 Feb 24.

Abstract

Exploration of alternative structures of the substituted piperidine or piperazine ring which are characteristic in most of the reported GPR119 agonists provided novel spirocyclic cyclohexane derivatives. The representative 17 with a high three-dimensionality exhibited potent agonistic activity (EC50 = 4 nM) with no CYP inhibitory activity (IC50 >10 μM). Compound 17 also displayed hypoglycemic activity with insulin secretion dependent on glucose concentration in an intraperitoneal glucose tolerance test in rats.

Keywords: GPR119 agonist; Spirocyclic structure; Type 2 diabetes.

MeSH terms

  • Animals
  • Cyclohexanes / chemical synthesis
  • Cyclohexanes / chemistry
  • Cyclohexanes / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Glucose / administration & dosage
  • Glucose / analysis
  • Glucose Tolerance Test
  • Humans
  • Hypoglycemic Agents / chemical synthesis
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology*
  • Injections, Intraperitoneal
  • Insulin / metabolism
  • Molecular Structure
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / metabolism
  • Spiro Compounds / chemical synthesis
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology*
  • Structure-Activity Relationship

Substances

  • Cyclohexanes
  • GPR119 protein, human
  • Hypoglycemic Agents
  • Insulin
  • Receptors, G-Protein-Coupled
  • Spiro Compounds
  • Cyclohexane
  • Glucose